NeuralCipher Research overview
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Misfolded proteins are pathological findings in some chronic neurodegenerative disorders including Alzheimer's, Parkinson's, and Huntington's diseases. Aging is a major risk factor for these disorders, suggesting that the mechanisms responsible for clearing misfolded proteins from the brain, the ubiquitin-proteasome system and the autophagy-lysosomal pathway, may decline with age. Although autophagic mechanisms have been found to decrease with age in many experimental models, whether they do so in the brain is unclear. This review examines the literature with regard to age-associated changes in macroautophagy and chaperone-mediated autophagy (CMA) in the central nervous system (CNS). Beclin 1, LC3-II, and the LC3-II/LC3-I ratio have frequently been used to examine changes in macroautophagic activity, while lamp2a and HSPA8 (also known as hsc70) have been used to measure CMA activity. Three gene expression analyses found evidence for an age-related downregulation of macroautophagy in human brain, but no published studies were found of age-related changes in CMA in human brain, although cerebrospinal fluid concentrations of HSPA8 were reported to decrease with age. Most studies of age-related changes in brain autophagy in experimental animals have found age-related declines in macroautophagy, and macroautophagy is necessary for normal lifespan in Caenorhabditis elegans, Drosophila, and mice. However, the few studies of age-related changes in brain CMA in experimental animals have produced conflicting results. Investigations of the influence of aging on macroautophagy in experimental animals in systems other than the CNS have generally found an age-related decrease in Beclin 1, but conflicting results for LC3-II and the LC3-II/LC3-I ratio, while CMA decreases with age in most models. CONCLUSION: while indirect evidence suggests that brain autophagy may decrease with normal aging, this issue has not been investigated sufficiently, particularly in human brain. Measuring autophagic activity in the brain can be challenging because of differences in basal autophagic activity between experimental models, and the inability to include lysosomal inhibitors when measuring the LC3-II/LC3-I ratio in postmortem specimens. If autophagy does decrease in the brain with aging, then pharmacological interventions and/or lifestyle alterations to slow this decline could reduce the risk of developing age-related neurodegenerative disorders.
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